We hypothesize that the early innate immune response to SIV initially serves to limit virus production but paradoxically, by recruiting CD4+ T cells to the site of infection, it likely also provides the cellular fuel in sufficiently high numbers enabling the virus to become a self-propagating infection. Once the initial founder populations have been established and local production of virus amplified, the virus quickly disseminates first to the draining lymph nodes of the female reproductive tract such as the inguinal lymph nodes. From the draining nodes it ultimately gains access to the blood stream, distal peripheral lymphatic tissues and by 10-14 days post inoculation SIV viral loads peak in the plasma and tissues throughout the body. The post peak decline in viral load is coincident with the development and expansion of an adaptive immune response, during the acute phase and this response may play a role in lowering viral replication to set-point levels. However, over time the constant stimulation of an immune response, which is not of sufficient quality or quantity to eliminate the virus, may (similar to the early innate response), provide target cells for the virus and ultimately contribute to the hosts demise. The hosts immune response to HIV/SIV induces a state of generalized immune activation. The level of chronic generalized immune activation has been shown to be a good predictor of disease progression. We will directly test the contribution of the early innate IFN&#61537; response at the mucosal portal of entry to the establishment, rate of dissemination and ultimately the outcome of SIV infection in RMs. To do this we will inhibit the biological activity of IFN&#61537; & &#61538; by treating rhesus macaques with an anti-IFN&#61537; receptor antibody (aIFN-&#61537;R) prior to and during the early stages of SIV infection. The study will be performed in 2 phases; Phase 1 will assess the effects of blocking INF&#61485;&#61472;&#61537; responses with an antibody to IFN-&#61537;R on the establishment and rate of SIV dissemination. Phase 2 will assess the effect of aIFN-&#61537;R on viral dynamics, MALT CD4+ T cell depletion, SIV-specific immune responses and disease progression.